What is the impact of dexamethasone on postoperative pain in adults undergoing general anaesthesia for elective abdominal surgery: a systematic review and meta-analysis

Background Previous meta-analysis of heterogeneous surgical cohorts demonstrated reduction in postoperative pain with perioperative intravenous dexamethasone, but none have addressed adults undergoing elective abdominal surgery. The aim of this study was to determine the impact of intravenous perioperative dexamethasone on postoperative pain in adults undergoing elective abdominal surgery under general anaesthesia. Methods This review was prospectively registered on the international prospective register of systematic reviews (CRD42020176202). Electronic databases Medical Analysis and Retrieval System Online (MEDLINE), Exerpta Medica Database (EMBASE), (CINAHL) Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science and trial registries were searched to January 28 2021 for randomised controlled trials, comparing dexamethasone to placebo or alternative antiemetic, that reported pain. The primary outcome was pain score, and secondary outcomes were time to first analgesia, opioid requirements and time to post-anaesthesia care unit (PACU) discharge. Results Fifty-two studies (5768 participants) were included in the meta-analysis. Pain scores ≤ 4 hour (h) were reduced in patients who received dexamethasone at rest (mean difference (MD), − 0.54, 95% confidence interval (CI) − 0.72 to − 0.35, I2 = 81%) and on movement (MD − 0.42, 95% CI − 0.62 to − 0.22, I2 = 35). In the dexamethasone group, 4–24 h pain scores were less at rest (MD − 0.31, 95% CI − 0.47 to − 0.14, I2 = 96) and on movement (MD − 0.26, 95% CI − 0.39 to − 0.13, I2 = 29) and pain scores ≥ 24 h were reduced at rest (MD − 0.38, 95% CI − 0.52 to − 0.24, I2 = 88) and on movement (MD − 0.38, 95% CI − 0.65 to − 0.11, I2 = 71). Time to first analgesia (minutes) was increased (MD 22.92, 95% CI 11.09 to 34.75, I2 = 98), opioid requirements (mg oral morphine) decreased (MD − 6.66, 95% CI − 9.38 to − 3.93, I2 = 88) and no difference in time to PACU discharge (MD − 3.82, 95% CI − 10.87 to 3.23, I2 = 59%). Conclusions Patients receiving dexamethasone had reduced pain scores, postoperative opioid requirements and longer time to first analgesia. Dexamethasone is an effective analgesic adjunct for patients undergoing abdominal surgery. Supplementary Information The online version contains supplementary material available at 10.1186/s13741-022-00243-6.

Conclusions: Patients receiving dexamethasone had reduced pain scores, postoperative opioid requirements and longer time to first analgesia. Dexamethasone is an effective analgesic adjunct for patients undergoing abdominal surgery.

Keywords: Dexamethasone, Postoperative pain, Abdominal surgery
Background Pain is a common postoperative problem and can be associated with physical and psychological sequelae. Glucocorticoids can modify the stress response and reduce inflammation. Dexamethasone, a commonly used antiemetic, interferes with the cyclooxygenase and lipoxygenase pathways through phospholipase inhibition and has been proposed to modulate postoperative pain in surgical patients (Moore, 2018). Two reviews, Waldron et al. and De Oliveira et al., established a reduction in postoperative pain from a single perioperative dose of dexamethasone in heterogeneous surgical cohorts with debated clinical significance (Moore, 2018;De Oliveira Jr. et al., 2011a;Waldron et al., 2013). Additionally, they demonstrated dexamethasone's opioid-sparing effects but produced conflicting conclusions regarding the dose-response relationship (De Oliveira Jr. et al., 2011a;Waldron et al., 2013). Therefore, the analgesic benefit of glucocorticoids in abdominal surgery remains unclear (Ahn et al., 2011;Holte & Kehlet, 2002). Waldron et al. excluded patients who received intrathecal or epidural local anaesthetics or opioids yet regional anaesthesia plays a key role in opioidsparing analgesia for major abdominal surgery (Waldron et al., 2013). Furthermore, patients who received multiple doses of dexamethasone were excluded potentially limiting their clinical significance considering the surgical stress response extends beyond the period of surgery.
Given the exclusion criteria in reviews to date, it is unclear if any benefit demonstrated from the use of dexamethasone in heterogenous cohorts can be translated into patients undergoing elective abdominal surgery.
Therefore, the aim of this review is to determine the effect of perioperative dexamethasone on postoperative pain in adults undergoing general anaesthesia for elective abdominal surgery.

Methods
This study was performed according to a prospectively registered protocol (CRD42020176202) and followed guidance from the preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement (Moher et al., 2009;Liberati et al., 2009;Research NIfH, 2020).
Randomised controlled trials (RCT) of adults, aged 18 or over, who received intravenous perioperative dexamethasone undergoing general anaesthesia alone or in combination with regional anaesthesia with pain as a primary or secondary outcome for elective abdominal surgery were included. Gastrointestinal, gynaecological and urological procedures were included but renal or transplant surgery was excluded. As the intention was to assess the impact of dexamethasone on postoperative pain, minor gynaecological procedures that were not considered to be painful for example diagnostic laparoscopy were excluded (Alexander, 1997). Studies were included if intravenous dexamethasone was given at any time, in any dose, either alone or in combination with other antiemetics with placebo or any combination of antiemetic drugs as the comparator. Other study drugs could be given provided the analgesic effect of dexamethasone could be isolated. The primary outcome of our review was pain scores reported on an 11-point numerical scale (0-10). Secondary outcomes for this study included time to first analgesia, opioid requirements and time to post anaesthesia care unit (PACU) discharge.

Literature search
Electronic databases Medical Analysis and Retrieval System Online (MEDLINE), Exerpta Medica Database (EMBASE), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Central Register of Controlled Trials (CENTRAL) and Web of Science were searched, with no language or date restrictions, for RCTs published up to January 28 2021. When available, a standardised search strategy to identify RCTs was used (Lefebvre et al., 2019) and the full search strategy was published (Research NIfH, 2020) (see Additional file 1). Grey literature and trial registers were searched as prespecified; however, due to the COVID-19 pandemic, the World Health Organisation (WHO) International Clinical Trials Registry Portal (ICTRP) was temporarily closed to external users and not searched as prespecified (World Health Organisation, 2020). The reference lists of identified studies and relevant systematic reviews were scanned for additional evidence.
Two authors, (CM and SJC), independently screened unblinded citations, assessed full texts for eligibility, extracted data, recorded on a predetermined data extraction form (see Additional file 2) and assessed bias at outcome level using Cochrane guidance (Sterne et al., 2019). When necessary, a third author (CO'D) mediated any disagreements.
When the specific surgical procedure was not stated and attempts to contact the author failed, we excluded minor painless surgical procedures based on the length of surgery, anaesthetic and surgical technique, length of hospital stay and postoperative analgesic requirements. Pain scores were defined as early (≤ 4 h), intermediate (4-24 h) and late (≥ 24 h) and pain scores presented as a range of times were allocated to the group they most closely corresponded, for example, 0 to 6 h was allocated to the early group. When multiple pain scores were presented for a single time interval, the latest pain score was extracted. Pain scores were assumed to be at rest when this was not stated and converted from a 0-100 to a 0-10 scale as required. Opioids were combined to achieve the total postoperative dose and converted to oral morphine equivalents (see Supplementary Table 1, Additional File 3). Time to first analgesia and PACU discharge were collected in minutes. Authors were successfully contacted for unpublished data or study clarification in seven studies (Bataille et al., 2016;Jo et al., 2012;Sanchez-Ledesma et al., 2002;Ko-Iam et al., 2015;Chen et al., 2020;D'Souza et al., 2011;Kirdak et al., 2008). Data was extracted as mean and standard deviation or converted using verified methods (Higgins & Deeks, 2019;Hozo et al., 2005;Luo et al., 2018;Wan et al., 2014). Studies containing multiple groups were combined into those with dexamethasone, irrespective of dose or timing, and those not containing dexamethasone. When the analgesic effect of dexamethasone could not be isolated, a subset of study data was included to exclude confounding analgesia.
Meta-analysis of outcome data using a random-effects model was performed using Review Manager ((RevMan) [Computer program]. Version 5.4, The Cochrane Collaboration, 2020) and presented as mean difference (MD) with 95% confidence intervals (CIs). Statistical heterogeneity was assessed using the method proposed by Higgins et al. (I 2 test) (Higgins et al., 2003).

Results
Database and trial registry searches revealed a total of 2160 citations. Altogether, 1846 irrelevant citations were removed, followed by 184 research and publication duplicates leaving 130 articles for eligibility assessment. Twelve articles by Fujii et al. and Schietroma et al. were excluded due to concerns over research validity and multiple retractions (Rasmussen et al., 2012;Carlisle, 2012;Scott, 2012;Myles et al., 2019). We were unable to obtain two full text articles and 13 non-English articles were removed. One hundred and three articles remained for full text eligibility assessment. Studies failed to meet the inclusion criteria and were excluded for the following reasons; 23 articles reported no pain outcomes, three studies were not RCTs, two studies had mixed surgical cohorts, participants did not receive general anaesthesia in three studies, there was no intravenous comparator in four studies and in one the analgesic effect of dexamethasone could not be isolated. Seven studies with minor surgery were excluded (Abreu et al., 2006;Asadollah et al., 2014;Lee et al., 2003;Ormel et al., 2011;Rajeeva et al., 1998;SS, 2007;Thomas & Jones, 2001). A further 12 studies were excluded; two used an alternative method of pain assessment and 10 presented inadequate data for analysis that we were unable to obtain through contacting the authors. Forty-eight full text articles remained, and four additional studies were included after reference list searching resulting in 52 studies with a total of 5758 participants articles (Fig. 1).
The final included studies are summarised in the characteristics of included studies table (Table 1). All 52 studies were RCTs of adult patients undergoing general anaesthesia for abdominal surgery published in English. The most common dose of dexamethasone used was 8 mg but ranged from 1.25 to 20 mg. Four studies presented the dose of dexamethasone in mg kg −1 and were transformed into total doses using the mean study weights or the average weight of an adult at the time and location of the study (De Oliveira Jr. et al., 2011b;Kassim et al., 2018;Lee et al., 2017;Rothenberg et al., 1998;Fryar et al., 2018). No studies administered multiple doses of dexamethasone, but six studies included two or more different doses of dexamethasone (De Oliveira Jr. et al., 2011b;Elhakim et al., 2002;Jokela et al., 2009;Liu et al., 1999;Murphy et al., 2014;Thangaswamy et al., 2010). A further two studies compared the same dose of dexamethasone at different times of administration (Lim et al., 2011;Wang et al., 2000). Opioid doses presented in mg kg −1 were converted in a similar manner to dexamethasone (Ko-Iam et al., 2015;Jokela et al., 2009;Pajunen et al., 2012).

Subgroup analyses
Subgroup analyses of general anaesthesia in combination with either central neuraxial blockade (GA + CNB) or regional anaesthesia (GA + RA) were previously documented (CRD42020176202) (Research NIfH, 2020). Patients received GA + CNB in three studies; spinal with intrathecal morphine (Sanchez-Ledesma et al., 2002), epidural administration of morphine and fentanyl (Yuksek et al., 2003) and a small proportion of both the intervention and control groups received an epidural in one study (Kurz et al., 2015). The subset of study data was not available in this study (Kurz et al., 2015). One study documented the use of regional anaesthesia with either transversus abdominal plane block or rectus sheath block (Regasa et al., 2020). Given the limited data, these predefined subgroup analyses were not undertaken.
The planned dosing subgroup analyses were undertaken for a single but not multiple doses of dexamethasone. Doses were grouped pragmatically into three categories to correspond with clinical practice; low dose  Time to first analgesia was increased with intermediate dose (MD 27.76;CI 13.96,41.55; I 2 98%; n = 1034) but low (MD 11.58; CI − 0.34, 23.5; I 2 89%; n = 462) and high dose had no impact (MD 25.44;53.12 Timing of administration subgroup analyses of dexamethasone were also performed. This was categorised as preoperative (before anaesthetic induction), intraoperative (anaesthetic induction and to extubation) and postoperative (after extubation). The timing subgroup analyses demonstrated a global reduction in pain scores from preoperative administration of dexamethasone for all pain scores both at rest and on movement. In contrast, intraoperative administration only reduced late pain scores at rest.

Conclusions
To our knowledge, this is the largest systematic review and meta-analysis investigating the effect of perioperative dexamethasone on postoperative pain in adults undergoing elective abdominal surgery under general anaesthesia and the first to demonstrate an important analgesic effect in this surgical cohort.
Our analyses demonstrated a statistically significant reduction in early, intermediate and late pain scores both at rest and on movement. Sub-group analyses revealed that intermediate dose (6.4-10 mg) effectively decreased pain at all time intervals both at rest and on movement. However, low dose (1.25-5 mg) only affected early pain scores at rest while high dose (11-20 mg) had no impact on any pain scores. Preoperative administration of dexamethasone demonstrated a global reduction on all pain scores. Intraoperative administration was more beneficial in reducing late pain scores at rest but failed to impact pain at any other time period. Dexamethasone also reduced the total postoperative opioid requirements and increased the time to first analgesia with intermediate dose (6.4-10 mg) and preoperative administration demonstrating the greatest impact. Time to PACU discharge was not altered by dexamethasone at any dose or time and is likely to be influenced by external factors (Samad et al., 2006). However, this is contrary to previous findings which have questionable clinical significance (Waldron et al., 2013).
Dexamethasone's established anti-inflammatory properties have ensured it is a widely used effective perioperative anti-emetic (Moore, 2018;Holte & Kehlet, 2002;De Oliveira Jr. et al., 2013). In abdominal surgery, glucocorticoids reduce pro-inflammatory mediators and phospholipase required for pain pathways allowing its analgesic benefits to be increasingly recognized (Moore, 2018;De Oliveira Jr. et al., 2011a;Waldron et al., 2013;Holte & Kehlet, 2002). Enhanced recovery pathways encouraging earlier mobility have boosted the demand for opioid-sparing multimodal analgesia in patients undergoing abdominal surgery (Gustafsson et al., 2019;Nelson et al., 2019;Nygren et al., 2012;Thorell et al., 2016). Dexamethasone has, therefore, an important role in postoperative analgesia with additional benefit for multimodal analgesic regimes in this patient population. However, full analgesic effect is unlikely from the commonly used lower anti-emetic dose and intermediate dose (6.4-10 mg) is necessary to produce global reductions in pain scores, increase time to first analgesia and reduce opioid requirements (Moore, 2018;De Oliveira Jr. et al., 2013). Additionally, timing of administration is crucial as the analgesic benefits of preoperative dexamethasone far outweigh administration at induction as recommended for antiemetic effect (Gan et al., 2020).
One of the major strengths of this review is inclusion of a large number of studies and participants of a relatively homogenous surgical population. This allows the results to inform future clinical practice and guidelines in moderate and major abdominal surgery. A previous systematic review failed to demonstrate a reduction in early pain scores on movement from dexamethasone administration, likely due to small numbers (Waldron et al., 2013). This new finding is potentially significant for enhanced recovery regimes where early movement after abdominal surgery is encouraged (Gustafsson et al., 2019;Nelson et al., 2019;Nygren et al., 2012;Thorell et al., 2016). In addition, investigation of dexamethasone's effect on intermediate pain scores is novel and provides further evidence of its analgesic effects (De Oliveira Jr. et al., 2011a;Waldron et al., 2013). Through subgroup analyses, we have provided clarification on the debated perioperative dosing and given strength to the previously suggested preoperative timing (De Oliveira Jr. et al., 2011a;Waldron et al., 2013). Despite demonstrating a globally statistically significant reduction in postoperative pain scores, it is important to remember that the clinical significance of this is uncertain. The increase in time to first analgesia and reduction in postoperative opioids is likely to have more clinical impact on patients undergoing abdominal surgery. When studies with regional anaesthesia were removed, a statistically significant reduction in postoperative opioids (MD − 6.87; CI − 9.70, − 4.05; I 2 89%; n = 3153) and increased time to first analgesia (MD 23.01; CI 11.14, 34.88; I 2 98%; n = 1521) remained.
There are a number of limitations in our review. Firstly, results could potentially be biased by selective reporting and missing outcome data, but the funnel plots were reassuring (Chen et al., 2020;D'Souza et al., 2011;Kirdak et al., 2008;Bala et al., 2014;Bilgin et al., 2004;Chu et al., 2008;Karaman et al., 2013;McKenzie et al., 1994;Ramesh, 2011;Wang et al., 2002;Zargar-Shoshtari et al., 2009). Secondly, as the latest pain score was extracted from each time interval, there could be significant variation in the timing which may explain some of the statistical heterogenicity in intermediate and late pain scores. Late pain scores varied from 24 h to 4 days, with later pain scores less likely to demonstrate statistical significance potentially influencing the results. The variation in timing of recorded postoperative opioid consumption, from 1 h to 5 days, may also account for some of the statistical heterogenicity. Thirdly, results from the high dose and postoperative subgroup analyses should be interpreted with caution given the low numbers available. In addition, we did not investigate the impact of adverse effects of dexamethasone administration as this has previously been done (De Oliveira Jr. et al., 2011a;Waldron et al., 2013;Polderman et al., 2018). However, when reported, adverse features reported were similar between intervention and control groups and not attributed to dexamethasone administration. Furthermore, pain was the primary outcome in less than half the studies but when analyses were restricted to studies with pain as the primary outcome all results remained statistically significant except late pain scores on movement. In addition, pain scores on movement were less likely to be reported potentially reducing the strength of the sensitivity analyses. Pain scores on movement should be the focus of future studies given the drive for postoperative mobilisation.
Additionally, due to lack of data, we were unable to perform our prespecified subgroup analyses GA + CNB and GA + RA. Dexamethasone may impact on postoperative pain in combination with general and regional anaesthesia, but it is unclear if this can be translated to the general surgical population (Chen et al., 2018;Fan et al., 2018;Pehora et al., 2017). It is our opinion that this question remains unanswered and should guide future research.
Unfortunately, nearly half of all studies were deemed high ROB, frequently due to selection of the reported result with failure to report all measured pain scores. As the majority of studies had a non-pain primary outcome, ROB assessment at study rather than outcome level would have impacted these results. ROB assessment highlighted issues with study methodology, with inadequate allocation concealment in nearly half of all studies, and trialists should be reminded of reporting guidelines for RCTs (Moher et al., 2010). Additionally, the type of analysis was infrequently documented, and we judged nearly half of all studies undertook a per-protocol analysis due to exclusions of protocol violations and postrandomisation participants for reasons not prespecified. Some exclusions are justified in a modified intention-to-treat (mITT) analysis, but we exercised caution using this label due to ambiguity over the definition (Abraha & Montedori, 2010;Gupta, 2011). We feel clarification of mITT criteria is essential to avoid subjectivity of future ROB assessments. However, the completeness of outcome data provides some reassurance over the safety and lack of adverse features of dexamethasone.
In conclusion, a single perioperative dose of intravenous dexamethasone reduces early, intermediate and late pain scores both at rest and on movement, opioid requirements and increases time to first analgesia in patients undergoing elective abdominal surgery. Preoperative administration of intermediate dose is likely to have the greatest impact on outcomes.